Calorie
restriction,
involves eating
about 30 percent
fewer calories
than normal
while still
getting adequate
amounts of
vitamins,
minerals and
other nutrients.
Aside from
direct genetic
manipulation,
calorie
restriction is
the only
strategy known
to extend life
consistently in
a variety of
animal species

In the last
year,
calorie-restricted
diets have been
shown in various
animals to
affect molecular
pathways likely
to be involved
in the
progression of
Alzheimer's
disease,
diabetes, heart
disease,
Parkinson's
disease and
cancer. Earlier
this year,
researchers
studying dietary
effects on
humans went so
far as to claim
that calorie
restriction may
be more
effective than
exercise at
preventing
age-related
diseases.

The findings
cast doubt on
long-held
scientific and
cultural beliefs
regarding the
inevitability of
the body's
decline. They
also suggest
that other
interventions,
which include
new drugs, may
retard aging
even if the diet
itself should
prove
ineffective in
humans. One
leading
candidate, a
newly
synthesized form
of resveratrol
-- an
antioxidant
present in large
amounts in red
wine -- is
already being
tested in
patients. It may
eventually be
the first of a
new class of
anti-aging
drugs.
Extrapolating
from recent
animal findings,
Dr. Richard A.
Miller, a
pathologist at
the University
of Michigan,
estimated that a
pill mimicking
the effects of
calorie
restriction
might increase
human life span
to about 112
healthy years,
with the
occasional
senior living
until 140,
though some
experts view
that projection
as overly
optimistic.

In almost
every instance,
the subjects on
low-calorie
diets have
proven to be not
just longer
lived, but also
more resistant
to age-related
ailments.

"In mice,
calorie
restriction
doesn't just
extend life
span," said
Leonard P.
Guarente,
professor of
biology at the
Massachusetts
Institute of
Technology. "It
mitigates many
diseases of
aging: cancer,
cardiovascular
disease,
neurodegenerative
disease. The
gain is just
enormous."

Researchers
at Louisiana
State University
reported in
April in The
Journal of the
American Medical
Association that
patients on an
experimental
low-calorie diet
had lower
insulin levels
and body
temperatures,
both possible
markers of
longevity, and
fewer signs of
the chromosomal
damage typically
associated with
aging.

These
studies and
others have led
many scientists
to believe they
have stumbled
onto a central
determinant of
natural life
span. Animals on
restricted diets
seem
particularly
resistant to
environmental
stresses like
oxidation and
heat, perhaps
even radiation.
"It is a very
deep, very
important
function," Dr.
Miller said.
Experts theorize
that limited
access to energy
alarms the body,
so to speak,
activating a
cascade of
biochemical
signals that
tell each cell
to direct energy
away from
reproductive
functions,
toward repair
and maintenance.
The
calorie-restricted
organism is
stronger,
according to
this hypothesis,
because
individual cells
are more
efficiently
repairing
mutations, using
energy,
defending
themselves and
mopping up
harmful
byproducts like
free radicals.

"The
stressed cell is
really pulling
out all the
stops" to
preserve itself,
said Dr. Cynthia
Kenyon, a
molecular
biologist at the
University of
California, San
Francisco. "This
system could
have evolved as
a way of letting
animals take a
timeout from
reproduction
when times are
harsh."

In a series
of studies, Dr.
Kenyon, of the
University of
California, San
Francisco, has
created mutant
roundworms that
live six times
longer than
normal, largely
because of a
mutation in a
single gene
called daf-2.
The gene encodes
a receptor on
the surface of
cells similar to
a receptor in
humans that
responds to two
important
hormones,
insulin and the
insulin-like
growth factor 1
or IGF-1.

Insulin is
necessary for
the body to
transport
glucose into
cells to fuel
their
operations. Dr.
Kenyon and other
researchers
suggest that
worm cells with
mutated
receptors may be
"tricked" into
sensing that
nutrients are
not available,
even when they
are. With its
maintenance
machinery
thereby turned
on high, each
worm cell lives
far longer --
and so does the
worm.

Many experts
are now
convinced that
the
energy-signaling
pathways that
employ insulin
and IGF-1 are
very involved in
fixing an
organism's life
span. Some
researchers have
even described
Type 2 diabetes,
which is marked
by insensitivity
to the hormone
insulin, as
simply an
accelerated form
of aging.

In yeast,
scientists have
discovered a
gene similar to
daf-2 called
SIR2, that also
helps to
coordinate the
cell's defensive
response once
activated by
calorie
restriction or
another external
stressor. The
genes encode
proteins called
sirtuins, which
are found in
both plants and
animals.

A mammalian
version of the
SIR2 gene,
called SIRT1,
has been shown
to regulate a
number of
processes
necessary for
long-term
survival in
calorie-restricted
mice.

Scientists
are now trying
to develop
synthetic
compounds that
affect the genes
daf-2 and SIRT1.

Several
candidate drugs
designed to
prevent
age-related
diseases,
particularly
diabetes, are on
the drawing
boards at
biotech
companies.
Sirtris
Pharmaceuticals,
in Boston,
already has
begun testing a
new drug in
patients with
Type 2 diabetes
that acts on
SIRT1 to improve
the functioning
of mitochondria,
the cell's
energy
factories.

While an
anti-aging pill
may be the next
big blockbuster,
some ethicists
believe that the
all-out
determination to
extend life span
is veined with
arrogance. As
appointments
with death are
postponed, says
Dr. Leon R. Kass,
former chairman
of the
President's
Council on
Bioethics, human
lives may become
less engaging,
less meaningful,
even less
beautiful.
Dr. Kass
recently wrote.
"Mortality makes
life matter."